Oral administration is a method by which a medicinal product can be taken relatively safely since a medicine can be taken naturally and simply in daily lives by oral administration and it is non-invasive. Since the digestive tract has a structure suitable for drug absorption and has large absorption surface area, development of an oral preparation as the medicinal preparation is desired. However, there are some problems which should be overcome for enabling oral administration of a drug.
One problem is possibility of degradation of a drug by enzymes in the digestive tract before migration into the general circulation. For solving this, deactivation of a drug in stomach can be prevented by an enteric-coated preparation technology or the like, thereby delivering the drug into the intestinal tract.
Another problem is insufficient permeation of a drug through the intestinal tract mucosal epithelium. Absorbability in the digestive tract is one important determination factor of the pharmacokinetics and the pharmacological activity of a medicinal product in oral administration. However, since a water-soluble high molecular medicinal product such as nucleic acids expected as the next-generation medicinal product shows extremely low digestive tract absorbability, administration thereof is limited to an intravenous injection method rather than oral administration, in clinical practice.
Studies using absorption promoters and additives for transiently increasing the substance permeability of a biological membrane have been conducted to date, for attaining an improvement in the absorbability of a medicinal product by the digestive tract. The absorption promoter includes surfactants, fatty acids and alcohols. The absorption promoters and the additives, however, have safety issues that absorption by the digestive tract is increased non-specifically by opening and closing of tight junction, the effect cannot be exhibited sufficiently because of dilution with water or the like in a biological body, mucous membrane disorders occur in the local, and the like. Therefore, the practical use thereof is limited to a suppository. These methods are insufficient for an improvement in the absorption efficiency of a high molecular medicinal product even if the methods can be applied to an improvement in the absorption efficiency of a low molecular medicinal product.
Further, studies of increasing absorption in the digestive tract using cell membrane-permeable peptides such as human immunodeficiency virus (HIV)-1 Tat peptide, HIV-1 Lev peptide, penetratin, transportan and arginine oligomer have also been conducted. There are peptides promoting absorption of insulin from the digestive tract in basic studies, however, its efficiency is still about 20% and there is no clinically applied peptide, thus, further efficient sequences are sought.
Furthermore, there is suggested also a transepithelial absorption promoter in which absorption of a coexistent drug is improved by binding a cell membrane-permeable peptide to a backbone polymer as a base material (Patent document 1).
In addition, a chitosan-modified liposome is developed (Non-Patent document 1). Its transport mechanism is mainly composed of permeation through intercellular gap, acting on F-actin, to weaken tight junction. However, transcellular transport is also said to be adsorptive endocytosis via mutual interaction with mucin. This is not yet clinically applied, too.
As a method of improving small-intestinal absorption of a high molecular medicinal product, a method combining a protease inhibitor and a drug carrier is suggested (Non-Patent document 2). In this method, degradation of insulin as a peptide/protein preparation can be suppressed 100% by a protease inhibitor. It is reported that bioavailability in rat oral administration is improved up to 10% by enclosing insulin in smart hydrogel as a drug carrier (Non-Patent document 3). The drug reaches small intestine, however, its absorption rate is not sufficient yet.
For this reason, a further excellent drug carrier which can be administered orally and intending an improvement in absorption in small intestine has been desired.